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Current Neuropharmacology, 2017, 15, 184-194

REVIEW ARTICLE

ISSN: 1570-159X eISSN: 1875-6190

Impact Common Neurogenetic Diagnosis and Meso-Limbic Manipulation of Factor: 3.753 Hypodopaminergic Function in Reward Deficiency Syndrome (RDS): Changing the Recovery Landscape

BENTHAM SCIENCE

Kenneth Blum1-6,8,11,12,14,*, Marcelo Febo1, Rajendra D. Badgaiyan7, Zsolt Demetrovics8, Thomas Simpatico2, Claudia Fahlke9, Oscar-Berman M10, Mona Li11, Kristina Dushaj11 and Mark S. Gold12,13

1Department of Psychiatry, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL, USA; 2Department of Psychiatry, University of Vermont, Burlington, VT, USA; 3 Division of Neuroscience Based Therapy, Summit Estates Recovery Center, Las Gatos, CA, USA; 4Dominion Diagnostics, LLC, North Kingstown, RI, USA; 5IGENE, LLC, Austin, TX, USA; 6Department of Nutrigenomics, RDSolutions, Inc., Salt Lake City, UT, USA; 7Division of Neuroimaging, Department of Psychiatry, University of Minnesota College of Medicine, Minneapolis, MN, USA; 8Department of Psychology, Eotvos Lorand University, Budapest, Hungary; 9Department of Psychology, University of Gothenburg, Göteborg, Sweden; 10Departments of Psychiatry and Anatomy & Neurobiology, Boston University School of Medicine and Boston VA Healthcare System, Boston, MA, USA; 11PATH Foundation NY, New York, NY, USA; 12Departments of Psychiatry & Behavioral Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA; 13Department of Psychiatry, Washington University School of Medicine. St. Louis, MO, USA; 14Division of Neuroscience Research and Addiction Therapy, The Shores Treatment and Recovery, Port Saint Lucie, FL, USA

Abstract: Background: In 1990, Blum and associates provided the first confirmed genetic link between the DRD2 polymorphisms and alcoholism. This finding was based on an earlier conceptual framework, which served as a blueprint for their seminal genetic association discovery they termed “Brain Reward Cascade.” These findings were followed by a new way of understanding all addictive behaviors (substance and non-substance) termed “Reward Deficiency Syndrome” (RDS). RDS incorporates a complex multifaceted array of inheritable behaviors that are polygenic. A R T I C L E H I S T O R Y Objective: In this review article, we attempt to clarify these terms and provide a Received: September 08, 2015 Revised: April 11, 2016 working model to accurately diagnose and treat these unwanted behaviors. Accepted: April 21, 2016 Method: We are hereby proposing the development of a translational model we term "Reward Deficiency DOI: 10.2174/1570159X13666160512150 Solution System™" that incorporates neurogenetic testing and meso-limbic manipulation of a 918 “hypodopaminergic” trait/state, which provides dopamine agonistic therapy (DAT) as well as reduced “dopamine resistance,” while embracing “dopamine homeostasis.” Result: The result is better recovery and relapse prevention, despite DNA antecedents, which could impact the recovery process and relapse. Understanding the commonality of mental illness will transform erroneous labeling based on symptomatology, into a genetic and anatomical etiology. WC: 184. Keywords: Dopamine homeostasis, genetics, reward deficiency solution system, Reward Deficiency Syndrome (RDS).

INTRODUCTION only to be a precursor to Norepinephrine, was indeed a neurotransmitter by itself having an important role in brain Nobel prize winners, Arvid Carlsson, Paul Greengard, function. Greengard received the Nobel Prize because he and Eric Kandel, supported initial studies on dopamine as a showed the role of Dopamine in the synapse and Kandel neurotransmitter playing a significant part in the Central received the Nobel Prize for his contribution to the role of Nervous system (CNS). Carlsson was rewarded for his seminal work in the 1950’s showing that dopamine, thought Dopamine in learning and memory [1]. The work of Carlsson lead to not only the successful treatment of Parkinson Disease, but depression and even *Address correspondence to this author at the Department of Psychiatry & McKnight Brain Institute, University of Florida, College of Medicine, Box Schizophrenia. However, it is accepted that by using the 100183 Gainesville, FL, USA 32610-0183; Tel: 352-392-6680; Fax: 352-392- strong dopamine D2 receptor agonist L-Dopa there are issues 8217; E-mail: [email protected] related to motor control and dyskinesia [2]. Moreover, the

1875-6190/17 $58.00+.00 ©2017 Bentham Science Publishers Current Neuropharmacology Common Neurogenetic Diagnosis and Meso-Limbic Manipulation Current Neuropharmacology, 2017, Vol. 15, No. 1 185 role of antidepressants involving transporter systems and brain neurotransmitter that regulates perception of welfare via inhibition of the catabolic enzymes Monoamine–Oxidase the balancing of D1/D2 receptors [17, 18]. The combination (MOA-A,B) and Catecholamine-Methyl-Transferase (COMT) of dopamine as well as additional neurotransmitters like for depression is fraught with many issues related to side serotonin, neuropeptides, and other dominant brain enzymes effects and even mood alterations [3]. Finally, the utilization is responsible for producing this sense of well being. For of an anti-psychotic agent like Haloperidol that block example, decreased levels of serotonin are connected to dopamines response at D2 receptors could result in severe episodes of depression. mood changes as well and they have significant side effects Opioids in the reward circuitry of the brain are [4]. With due respect of these important findings still particularly connected to feelings of well being [19]. The important in today’s medical arsenal against these intrusive multiplex of such neurotransmitters are produced in the brain brain disorders, we can improve on these important medicaments. Interestingly, prior to 1968, little was known and so are their receptors through transcription process involving mRNA [20]. We are cognizant that there are many about the role of Dopamine and for example, ethanol abuse, associations of non-coding microRNAs (miRNAs) in all intoxication and clinically induced alcoholism. However, addictions. following the development of the Institutes of both drug abuse (National Institute of Drug Abuse) and alcoholism It is known that miRNAs are small non-coding RNAs (National Institute of Alcohol Abuse & Alcoholism) by the that function as translational repressors and represent an National Institutes of Health, the understanding of how these important element in cellular development as well as mental diverse addictive substances (e.g. glucose, alcohol, cocaine, illness. MicroRNA sequences and their target sites in heroin, nicotine, etc.) pharmacologically act, especially in miRNAs reveal a degree of commonality across species. the CNS and their commonality of neuro-functionality across It has now been adequately researched and found that a mental illness has been a wonderful work in progress [5]. single miRNA can recognize the 3'untranslated region of miRNAs in a sequence- specific manner to repress the Since the 1960’s and 70’s, the role of Dopamine was beginning to entice scientists and it was not until 1969 that protein expression of hundreds of targeted miRNAs. Most importantly, the human genome encodes more than 1000 the very first Neuroscience Society meeting occurred, miRNAs which effects over 60% of mammalian and human consisting of less than 100 members. In fact, Blum [6] was transcripts. Current data proposes that miRNAs control the first to show the role of dopamine at the neuromuscular expression of mu opiate receptors and in fact it is known that junction revealing that tremors could occur as a motor an opiate agonist like morphine and fentanyl can alter response to dopamine. This had relevance to the role of dopamine in Parkinsonism. Other work by Blum et al. [7-9] specific miRNAs signaling as well. The interaction between specific miRNAs and opiates and their respective receptors revealed that dopamine played an important role in will impact not only cell development, but analgesia, pain alcohol withdrawal symptomatology similar to morphine tolerance, and addiction [21]. He and Wang [22] suggested withdrawal. This served, along with the seminal work of that the let- 7 family of miRNAs is a critical regulator of mu Davis and Walsh [10], as the basis of common mechanisms. opiate receptor function in opioid tolerance. In 1977, Blum edited a book “Alcohol & Opiates” devoted to common mechanisms between these two seemingly Most et al. [23] has suggested that miRNA manipulation diverse chemical structures [11]. Melchoir and Myers in the may cause cocaine-seeking behavior, reward processing of mid 70’s also showed genetic differences in ethanol drinking cocaine, and self-administration rates of alcohol – all of various rat strains utilizing methods to destroy addiction-related behaviors. It has been adequately shown that serotonergic and dopaminergic pathways [12]. Following miR-212 causes a level of susceptibility in cocaine addiction. these earlier studies, Dackis & Gold developed the concept This is supported by a number of findings: of the “dopamine depletion hypothesis” specific for cocaine addiction [13]. Over a five-year period, there has been a 1) Compulsive cocaine-related behaviors are caused by plethora of research devoted to the role of neurotransmitters increased miR-212 manifestation within the rat dorsal and brain function [14]. During this time, Blum & striatum; 2) increased miR-212 manifestation protects from Kozlowski [15] developed and published on the concept they cocaine addiction, because virus interference within striatal coined “Brain Reward Cascade,” which served as a blue miR-212 reduces cocaine rat ingestion; 3) miR-212 has print for the first identification of the link between the shown amplified striatal cAMP response element-binding dopamine D2 receptor (DRD2) gene Taq A1 allele and protein (CREB) signaling via relevant pathways to activate severe alcoholism [16]. Raf1 kinase; and 4) miR-212 regulates cocaine ingestion by inhibiting striatal delivery of methyl CpG binding protein 2 Blum et al. [15] conceived “Reward Deficiency Syndrome” (MeCP2), lowered protein concentrations of brain-derived (RDS), which results from issues occurring during the neurotrophic factor (BDNF) and potential alteration of “Brain Reward Cascade” [15] explicitly associating atypical dopamine release and therefore attenuates motivation for cravings and poor executive function (decision-making). cocaine abuse [24]. The RDS concept included several reward gene deficits such as dopaminergic, serotonergic, endorphinergic, Undoubtedly, cocaine, heroin, amphetamines, and catecholaminergic, gabaergic, adrenergic, opioidergic, alcohol promote continual neuroadaptive adjustments by cholinergic, as well as many second messengers across increasing certain gene regulative pathways advancing prefrontal cortex and meso-limbic systems. Following many towards addiction. The commonly known ‘reward pathway,’ studies, it is generally agreed that dopamine is a dominant or the synaptic elasticity of the mesolimbic dopaminergic 186 Current Neuropharmacology, 2017, Vol. 15, No. 1 Blum et al. organization, is critical for drug dependence. Clearly, miR- data indicates that the overconsumption of food may cause 16 creates flexibility in serotonin transporter construction; similar addictive neuroadaptive responses in the brain’s miR-133b is uniquely manifested within midbrain dopaminergic reward systems and pushes towards compulsive eating neurons, and controls the creation of tyrosine hydroxylase habits. The authors propose that obesity and drug addiction (rate-limiting enzyme) and the dopamine transporter; miR- are related to common hedonic mechanisms [31]. 212 influences creation of striatal brain-derived neurotrophic factor (BNDF) and synaptic elasticity following chronic It has been recognized that some researchers have found cocaine abuse [25]. selective BDNF deficiency in a mouse ventromedial hypothalamus (VMH), which caused hyperphagic behavior Understanding these basic facts and concepts provides a and obesity. Cordeira et al. [32] observed ventral tegmental framework illustrating the realization that non-substance manifestation of BDNF and TrkB mRNA in wild-type mice, and substance related addictive behaviors along with a caused by the ingestion of appetizing, increased fatty foods. number of psychiatric illnesses such as major depression, schizophrenia and potentially bipolar disorder might have Additionally, deficits in the nucleus accumbens (NAc) common anatomical and genetic antecedents. The importance and dorsal striatum dopamine release and regular release in here is to lay down some findings that reveal common shared the NAc crux occurred after depletion of central BDNF in neurogenetic and other structural brain elements that may be the brain slices of mice found in amperometric recordings. important for therapeutic targeting and relapse-prevention, in Lobo et al. [33] found that suppression of cocaine reward terms of drug and non-drug repetitive behaviors. In order for was activated by D2+ neurons, imitating TrkB loss, but one to feel good the complex interaction of many genes and occurred with contrasting effects prompted by D1+ neuron transcription processes of these particular genes, ultimately activation. These data allows further understanding of D1+ control the brain’s dopaminergic actions within its reward and D2+ neuronal activity molecular control and also the center or mesolimbic center, or particularly the nucleus influence these cells have on cocaine reward. accumbens (NAc) and through resting state functional The DRD2 is commonly correlated with hedonism, while connectivity allows Homo sapiens to make good decisions the DRD2 A1 allele has been denoted as the reward gene [16]. deriving from frontal cortices activation. Research indicates that a three-way collaboration occurs between deficiency of dopamine receptors, susceptibility to NEUROCHEMICAL COMMONALITY OF SEEKING alcoholism, and decreased reward sensitivity. This BEHAVIOR relationship is dependent on individual genetic features, with As mentioned previously, RDS is currently evolving as specific ethnic groups having an increased propensity toward the conventional understanding for the connections between alcoholism compared to other groups [34]. DRD2 is a impulsive, compulsive, and addictive behaviors, known as prominent component of neuropsychiatric disorders and “process addictions” [26], in which Blum et al. [27] employed conditions, as well as alcoholism and other addictions Bayes' theorem to forecast future substance-seeking and (PUBMED 3,886 articles obtained 4/18/15). The dopamine deviant behavior. Brain reward mechanisms in the D2 gene, its receptor, including the TaqI A1 allele may also mesolimbic system have played a role in the dopaminergic play a role in antisocial personality disorder, obesity, structure, and more so, the DRD2 gene. Deviant substance gambling, and analogous [4] characteristics such as high (drug, tobacco, alcohol, and food) pursuing actions can be novelty seeking, and other psychiatric conditions [35]. The attributes of D2 dopamine receptor dysfunction. Years of mesocorticolimbic dopaminergic pathway system often research since the initial findings of Blum’s group [16] point mediates the strengthening of drugs abused, and may very to genetics playing a part in making an individual susceptible well take part in other addictions, including alcoholism [36]. to substance pursuance. It is our suggestion that multiple alternatives of DRD2 A1 allele may serve as genetic factors RDS and its resulting drug pursuing behaviors are caused in suspecting addiction (Blum et al. 1996). In this particular by the dysfunction of the mesocorticolimbic dopamine study, the anticipated assessment for those carrying the reward system (perhaps initiated by particular genetic DRD2 Taq A1 allele and their future RDS actions was 74%. variants). To reiterate, RDS indicates interruptions in the Many studies have taken a stand along with this report, reward cascade and subsequent abnormal behaviors, all maintaining the link between food craving and drug craving caused by genetic and environmental effects with the realization that all roads lead to dopamine [37]. Alcohol behavior via neuroimaging [28, 29]. and other commonly abused drugs, including positive The dopamine D2 receptor remains to be a major player reinforcers, trigger the dopamine activation and neuronal in RDS behaviors, despite the involvement of other genes release, which may reduce negative emotions and please [30]. Johnson and Kenney observed compulsive feeding unusual cravings. In the event of a D2 receptor deficiency or behavior only in obese rats, which was tracked via resistant absence, predisposed persons are at an increased risk of food consumption to harshly habituated stimuli. In obese several addictive, compulsive, and impulsive actions. While rates, striatal dopamine D2 receptors were down-regulated, additional neurotransmitters (e.g., gamma-aminobutyric acid as had been similarly described in humans experiencing (GABA), glutamate, and serotonin) can define rewarding addiction. Furthermore, the acceleration of the creation of and motivating ethanol effects, dopamine may be important reward deficiency and the start of eating compulsion in rats for drug initiation and returning to drug use after prolonged with availability to increased fatty food was caused by abstinence [38]. Lentivirus- mediated downfall of striatal D2 receptors. These Common Neurogenetic Diagnosis and Meso-Limbic Manipulation Current Neuropharmacology, 2017, Vol. 15, No. 1 187

REWARD GENES COMMONALITY FOR PRE- transport chain, signal transduction, synaptic transmission, DISPOSITION TO ADDICTIVE BEHAVIORS AND are responsible for addictive behaviors and provide DEPRESSION information regarding shared genetics. Along similar lines Levey et al [43] employed the translational Convergent Understanding the role of many neurotransmitter related Functional Genomics (CFG) in order to identify the genes and their interaction with respective receptors alcoholism genes via gene combination of a Genome-Wide regulated by appropriate vesicle storage, synthesis and Association Study (GWAS) data taken from German release mechanisms is tantamount to developing successful alcoholic population as well as alcoholism from USA therapies. The realization that the chemical structure of samples. While they found only nominal significance in the various drugs of abuse is dissimilar and quite diverse, while German cohort, when they chose the top CFG genes – eleven the basic neurobiology of these substances has many has a nominal significance in terms of predicting alcoholism similarities especially when RDS behaviors are considered. (P <0.041). The main CFG alcoholism gene from the first [11]. Since the early 90s, global research into the discovery stage, synuclein alpha (SNCA) [helps regulate neurological and neurogenetic mechanisms and the interplay dopamine] stayed as the initial gene even after stress- between many genes and the addictive process has paved the sensitive animal model cross-verification. Following way for the development of accurate genetic tests to identify extensive research Levey et al [43] correctly suggested that and provide risk stratification. the compelling genetic overlay with other neuropsychiatric It is well accepted that neuropsychiatric disorders are disorders provided a foundation for comorbidity and dual considerabley hereditary, with support implying that these examination, and as such, introduces alcoholism in a greater disorders have in common, a coinciding series of neuro- background of modifying the psychological panorama, molecular and neuronal foundations. These disorders include which includes RDS. attention deficit hyperactivity disorder (ADHD), autistic In addition Pearson-Fuhrhop et al. [44] were able to link spectrum disorders (ASD), anxiety disorders (Anx), bipolar a number of dopamine genes and associated polymorphisms disorder (BD), depressive disorder (DD), and schizophrenia to depression risk. In their study, five genes with functional (SCZ) among others. Using GWAS studies, Lotan et al. [39] polymorphisms were identified in synaptic dopamine found the most common grouping of genes in five of six possibility (COMT and DAT) were combined together with disorders included: ANK3, AS3MT, CACNA1C, CACNB2, dopamine receptor binding (DRD1, DRD2, DRD3) to create CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, a genetic risk score. They found that depression evidence SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Together, (β=−0.80, p=0.003), with decreased dopamine genetic these genetic factors are responsible for 20-30% of the addiction risk scores (signifying reduced dopaminergic genetic load. However, in a recent meta –analysis conducted neurotransmission), was related to the genetic addiction risk by Gatt et al. [40] considering the same set of psychiatric score overall, forecasting increased levels of depression. disorders as Lotan et al. [39] they found 13 genetic variants Importantly, they suggest that sequential difference appearing were mutually shared among multiple disorders (APOE e4, in several genes that control dopamine neurotransmission ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA can effect depressive symptoms, especially in terms of G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, HTR1A addiction. This work is in agreement with Blum’s group in C1019G, MTHR C677T, MTHR A1298C, SLC6A4 5- unpublished studies showing that a very specific panel of HTTLPR, SLC6A4 VNTR and TPH1 218A/C). reward genes and associated risk alleles causing a hypo- dopaminergic trait significantly predicted Addiction Severity While the above seems relevant for psychiatric disorders Index (ASI –Media Version) for both alcoholism (p<.004) excluding addiction, others have suggested other shared and drugs (P<0.05). candidate genes. Levran et al. [41] evaluated 801 African Americans and the relationship between 98 individual ABNORMALITIES OF NEUROANATOMICAL nucleotide polymorphisms and 13 dopamine-linked genes STRUCTURES ACROSS RDS CONDITIONS occurring with heroin addiction (OD) and/or cocaine addiction (CD). They found separate-marker analyses We are entering a new era of genomic medicine and rendered important indications for connections of 24 SNPs in neuroimaging and as such our understanding of brain DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT functions especially as it relates to mental illness remarkably and CSNK1E. A DRD2 7-SNPs haplotype that contained is providing new fundamental answers to age old questions SNPs rs1075650 and rs2283265, observed as modifying of “Nature (neurogenetics) vs. Nurture (neuro epigenetics).” D2S/D2L merging, was specified in both dependencies. The Most recently, Goodkind et al. [45] provided some important COMT Val158Met allele was correlated to defense from answers related to the fact that while psychiatric examinations OD. This finding was not significant following multiple are determined by groups of distinct symptoms, genetic and testing and while it suggests the importance of these clinical investigations locate comparisons across a large candidate genes, appropriate utilization of a very specific set range of diagnoses. This new work suggests that familiar of alleles maybe causing the loss of significance. According to neurobiological substrates can occur in different mental Li et al [42] their products demonstrated that amphetamine conditions. Specifically, they found a voxel-based morpho- feedback, diabetes mechanisms, dopamine receptors, energy metry meta-analysis of 193 studies composed of 15,892 metabolism, glucose control of insulin release, locomotor subjects across 6 different diagnostic bodies (addiction, behaviors, mitochondrial electron transport, negative control anxiety, bipolar disorder, depression, obsessive-compulsive of cell movement, NGF signaling, respiratory electron disorder, and schizophrenia), in which loss of gray matter 188 Current Neuropharmacology, 2017, Vol. 15, No. 1 Blum et al. met across diagnoses in 3 brain areas: the dorsal anterior investigation in this arena involves dopaminergic genetics. cingulate, left insula, and right insula. Further work from Alcoholism associated with the TaqIA polymorphism of the their laboratory also found that decreased gray matter was dopamine D2 receptor (DRD2) gene has been closely correlated to poor executive functioning. Goodkind et al. [5] observed [16], and the TaqI A1 allele appears to be over- have found an important hallmark network revealing that represented in alcohol-dependent individuals [49, 50]. This across psychiatric diagnoses there is a commonality of allele is also linked to a significantly higher mortality rate of abnormalities associated with an anterior insula/dorsal individuals who abuse alcohol [51]. Dahlgren et al. [52] anterior cingulate-based system, which may reveal deficiency found that 89% (16/18) of carriers of the A1 allele reported of executive functions seen across diagnoses including relapse, in contrast to 53% (17/32) of non-carriers (P = 0.01; complex RDS behaviors [45]. odds ratio = 7.1). They suggested that despite this small number and the first report, an increased relapse rate Other works from Oscar-Berman’s group support these associated with the Taq1 allele seems likely. Other work concepts and show the commonality of brain volume revealed that in terms of nicotine dependence that other abnormalities in both smoking and alcoholism. Specifically, dopaminergic genes such as the dopamine –beta – hydro- Luhar et al. [46] provided clear evidence linking brain xylase gene (rs1541333) has also been tied to relapse [53]. irregularities and poor performance on neuropsychological exams to alcoholism and smoking (separately and together). There are numerous studies involving many reward genes They show that compared to non-smoking/non-alcoholics, across many drugs of abuse and subsequent clinical smoking alcoholics had a number of volumetric brain outcomes relative to relapse behavior [54-62]. Similarly, abnormalities: the amygdala, lateral ventricle, pallidum, others have discussed the possible role of specific genes parahippocampal and temporal pole areas, pre- and para- (such as the DRD2 and associated polymorphisms) as a central frontal cortical areas, rostral middle frontal white potential cause for relapse, expanding their view to define a matter, ventral diencephalic region. One primary issue psychological basis for such relapse impacted by genetic related to these significant findings is that carriers of brain antecedents [63]. Others have discussed similar genetic volume abnormalities show reduced executive function and antecedents concerning gambling behavior as well [64]. decision-making abilities, which could impact both drug and With this new information are we in a position to provide non-drug seeking addictive behaviors and subsequent a genomic-based solution to impact relapse behavior in a relapse. Other work from Ruiz et al [47] revealed that effects clinically meaningful way. The answers may reside in of alcohol particularly on white matter and ventricular embracing a nutrigenomic approach. volumes are gender distinctive, with alcoholic females exhibiting the most change in frontal, temporal, ventricular, DOPAMINERGIC ACTIVATION THROUGH NUTRI- and corpus callosum regions, while males exhibited responses GENOMICS primarily in the corpus callosum. There is much research on utilizing nutritional therapy to This work has been highlighted because in that in any RDS-related health consequences. However, there is given year, nearly 20% of Americans exhibit symptoms that significantly less exploration in research on biochemical meet criteria for a psychiatric illness diagnosis. The goal is to control of neurotransmitters within the neural reward system shift the emphasis from symptomatology to neuropsychiatric and genetic polymorphic identification [65]. Li et al. [66] trajectories involving etiological genetic mechanisms, integrated 2,343 items of evidence from peer-reviewed epigenetics and genomic-based solutions especially in publications from 1976 to 2006 that linked specific genes children [48]. and respective chromosomal regions to addiction by single- gene strategies microarray, proteomics, or genetic studies. In NEUROGENETICS OF RELAPSE these studies, Li et al. (2008) found 1,500 human addiction- Homo sapiens are physiologically and biologically related genes and created the first molecular database of its motivated to engage in behavior resulting in pleasure, such kind for addiction-related genes, KARG (http://karg.cbi.pku. as gluttony, consumption of alcohol, and sexual intercourse. edu.cn). Li et al. (2008) then showed a meta-analysis of 396 Abnormal impairment of these behavioral inclinations results genes supported by at least 2 evidence items to identify 18 in impulsive, compulsive, and addictive behaviors further molecular pathways, covering both upstream and downstream dictated by genetic predispositions. While there are a variety signaling events. Five molecular pathways for four different of genetic variations that control mesolimbic activity, categories of addictive substances were identified as common polymorphisms of the serotonergic-2A receptor (5-HTT2a), mechanisms that may be components of shared reward and dopamine D2 receptor (DRD2), and the Catechol-o-methyl– addictive behavior. Among the five pathways were two new transferase (COMT), GABA receptors (A, B Units) and mechanisms: the GnRH signaling pathway and gap junction. many other genetic combinations predispose individuals to These two pathways were formulated into a potential increased compulsive cravings and similar impulses that molecular network of addictive behavior and they observed precede relapse. that both fast and slow positive feedback loops are linked through CAMKII, which could explain the irreversible Understanding the neurogenetics of relapse from all aspects of addiction. Notably this motif centers around addictive behaviors will be most beneficial clinically and dopaminergic and glutaminergic genes. Indeed, the could provide new therapeutic targets to prevent reinstatement dopamine molecule propagates behavioral responses of of drug and non-drug seeking behavior. One avenue of pleasure and stress-induced coping mechanisms. Common Neurogenetic Diagnosis and Meso-Limbic Manipulation Current Neuropharmacology, 2017, Vol. 15, No. 1 189

In light of this evidence, we wanted to evaluate the This method, which is both natural and therapeutic, may process of DNA-manipulation in diet and nutrition-based induce dopamine release, potentially resulting in the solution wellness and weight management. This study induction of D2-directed mRNA and enhanced proliferation genotyped 1,058 individuals who were administered with a of D2 receptors. Blum and Gold further hypothesized that patented nutraceutical based on polymorphic outcomes. In a the proliferation of D2 receptors in turn will induce the subset- simple t -tests comparing a number of parameters diminishing of drug-seeking behavior. Pharmacological before and 80 days after nutraceutical were performed. There methods have demonstrated limited success because such were notable results for weight loss, appetite suppression, agents are focused solely on the maintenance or interference snack reduction, decreased sugar cravings, decreased late of feelings of pleasure or euphoria post drug use rather than night eating (all P<0.01), increased perception of overeating, the individuals’ existing dopamine system deficits. Future improved sleep quality, increased happiness (all P<0.05), neuro-imaging studies may confirm these patterns, though and improved energy (P<0.001). Polymorphic correlates for recent studies propose a variety of potential therapeutic specific genes were obtained (LEP, PPAR-gamma2, and approaches including the targeting of the heteromeric A MTHFR, 5-HT2A, and DRD2 genes) with positive clinical (2A)-D (2) receptor complex [76]. parameters. Of these results and polymorphisms, only the DRD2 gene polymorphism (A1 allele) demonstrated a UNDERSTANDING COMMON THERAPEUTIC significant Pearson correlation with treatment days (r=0.42, TARGETS AND ISSUES P=0.045) This two -fold increase is a critical genotype for In terms of future targets to prevent cocaine relapse for compliance in treatment [67]. example, it is well known that the reinforcing and rewarding FUTURE PERSPECTIVES properties of cocaine are attributed to its ability to increase dopaminergic transmission in NAc. Moreover, this action Decades of peer-reviewed and established research on the reinforces drug taking and seeking and leads to long-lasting mesolimbic system have shed light on the mechanics of the associations between the rewarding effects of the drug and addictive brain and other underlying neurogenetic the cues associated with its availability. One important key dispositions. The mesolimbic system is the site of the brain to preventing relapse is to target dopamine receptors in the in which sensations of pleasure, perceived happiness and NAc. Dopamine produces these effects by controlling the well-being occur [68] and has been appropriately named, the activity of two subpopulations of NAc medium spiny “reward center.” Chemical messengers such as enkephalins, neurons (MSNs) that are defined by their predominant GABA and dopamine (DA), combine to release DA at the n. expression of either dopamine D1 or D2 receptors. Research accumbens (NAc). It has been established that genes dictate has demonstrated that optogenetically stimulating D1 MSNs the synthesis, storage, metabolism, receptor formation promotes reward, whereas stimulating D2 MSNs produces and neurotransmitter catabolism. Certain polymorphic aversion or attenuation of drug seeking. It is believed that variations may lead to an impairment of neurophysiologic acute administration of cocaine stimulates D1 receptors and events leading to the release of DA. This event series of is promotes reward. However, chronic cocaine exposure referred to as the “Brain Reward Cascade” [15, 69]. The deregulates these D1 signals to both prevent extinction and disruption of this cascade can ultimately precede a facilitate reinstatement of drug seeking to drive relapse. dysregulation and/or dysfunction of DA. Any impairment in These data elucidate the responses of D1- and D2-type the function of DA, the “pleasure molecule” and “anti-stress MSNs in NAc to acute cocaine and during the formation of molecule,” may result in reward deficiency and subsequent context-reward associations and define how prior cocaine aberrant substance-seeking behavior. exposure selectively deregulates D1 signaling to drive In a number of articles we have suggested a novel relapse [77]. approach that could have clinical importance called “Reward In addition, it has been discovered by Epstein’s group Deficiency Solution System™” [70] and provided rationale that carriers of the Met/Met genotype of the COMT gene had for the coupling of genetic testing [71], exploration of various a greater intensity of the novelty-seeking trait than carriers of treatment approaches utilizing Comprehensive Analysis of the Val/Val and Val/Met genotypes, though this association reported Drugs (CARD) ™ [72] and incorporation of a was seen only in women. Furthermore, the presence of the C genomic-based putative dopaminergic agonist KB220z allele of the DRD4 gene in carriers of the Met/Met genotype that has been shown to restore resting state functional showed high levels of extraversion and hypomania [78]. connectivity in abstinent heroin addicts [73]. Two major Other work by Noble’s group observed that total Novelty therapeutic platforms involving anti-drug vaccines [74] and Seeking score of the Tridimensional Personality Questionnaire gene therapy [75] have also been recently addressed with (TPQ) was significantly higher in boys having, in common, cautious consideration. all three minor (A1, B1, and Intron 6 1) alleles of the DRD2 We are cognizant that research in the Recovery field, in compared to boys without any of these alleles. Additionally, general, has revealed poor outcomes, notably in relapse boys with the DRD4 7 repeat (7R) allele also had a prevention and continued drug-seeking behavior [17]. significantly higher Novelty Seeking score than those Furthermore, Blum and Gold [17] proposed a new precedent without this allele. Finally, the combined DRD2 and DRD4 in clinical care and aftercare that incorporates genetic testing polymorphisms contribute more markedly to this behavior to identify risk alleles together with D2 receptor stimulation than when these two gene polymorphisms are individually using a neuroadatogen amino acid precursor enkephalinase- considered [79]. catecholamine-methyltransferase (COMT) inhibition therapy. 190 Current Neuropharmacology, 2017, Vol. 15, No. 1 Blum et al.

Importantly, a number of studies have suggested that cingulate, and cerebellum. In addition, both groups have DRD2/ANKK1 TaqIA genotype predicted smoking negative functional connectivity between the DLPFC and the initiation and subsequent use [80]. In fact, Doran et al. [80] orbitofrontal cortex. However, the AD subjects have positive showed that logistic regression indicated that the A1 allele functional connectivity between the DLPFC, temporal was associated with initiation (p = .003). This effect was lobe, and striatal areas, while IGD subjects have negative partially mediated by sensation seeking and negative functional connectivity between the DLPFC, temporal lobe, urgency. This takes on even more significant meaning when and striatal areas. Understanding these differences may you consider the work of others [52] showing that DRD2/ provide important differential therapeutic targets. ANKK1 TaqIA genotype A1 allele was high in subjects who relapsed with alcohol compared to A2 carriers. In addition, CONCLUSION Iordanidou et al. [81] showed significant association between It is known that specific drugs of abuse and neuro- 5-HT (2C) receptor gene polymorphisms and smoking pathways link up in the genome to effect miRNA biological initiation in male Caucasian subjects, but not in all races functioning in its relation to neurotransmission, enzymes that tested. Work by Grzywacz et al. [82] further confirm take part in neurotransmitter metabolism, and particular statistically significant associations between SNP in exon 8 neuronal receptors known for inducing feelings of well-being A/G in the DRD2 gene and alcohol withdrawal syndrome in human and nonhuman animals alike [92]. Dopaminergic with seizures, and between SNP in promoter -141 C I/D in alteration and manipulation of direct striatonigral and the DRD2 gene and early onset of alcohol dependence (AD). indirect striatopallidal pathways in the basal ganglia are vital Specifically, the A/A genotype in the exon 8 A/G poly- factors in rewarding and adverse patterns and drug addiction morphism is a positive predictive factor for the presence or [93]. In order to determine how the basal ganglia processes the lack of seizures in alcohol withdrawal syndrome. The and integrates data through these specific pathways, other A/G genotype is possibly a protective factor for this AD researchers have created a reversible neurotransmission phenotype. The authors suggest that dopamine receptor 2 obstructive technique, in which pathway transmission is gene polymorphisms are associated with alcohol addiction impeded by particular expressions of transmission-blocking and alcohol withdrawal syndrome. These results provide tetanus toxin in a doxycycline- dependent approach [94]. rationale for therapeutic intervention. These outcomes have shown that the synchronized variation Another important issue is how to treat RDS behaviors of these pathways is imperative for dopamine-mediated that are drug and non-drug related. There are those who acute psycho stimulant activity. Nonetheless, this variation support the view that the best approach to treat RDS is to has transferred its role between the direct pathway of reward attenuate the release and function of dopamine. This would feedback and cocaine stimulation and the indirect of aversive include substances that act as antagonists of dopamine behavior. These two pathways therefore have two separate function like naloxone/naltrexone and others approved by roles: the direct pathway is responsible for categorizing the the FDA as Medication Assisted Treatments (MATs) [83]. appropriate rewarding stimuli from non-appropriate ones and For the most part, MATs and/or antagonists of the dopamine the indirect pathway for increased memory formation in system have systematically failed [84]. In terms of RDS order to evade aversive stimuli. While we agree with this patients having low dopamine tone, there are a number of information, we also probe the role abused drugs have on studies involving measurement of tonic dopamine in cocaine mRNA within these pathways. This notion continues to be addicts [85] and resting state dopamine tone in ADHD [86]. investigated by our laboratory and will hopefully become the In the former case, it has been shown that as dopamine is subject of many future papers. However, we are indeed reduced, there is escalation of cocaine abuse [85]. In the proposing a novel approach challenging the entire recovery latter case, it has been shown that the dopamine tone in field to incorporate the following: Genetic Addiction Risk ADHD is reduced compared to non-ADHD controls [86]. Score (GARS) ™ for appropriate RDS diagnosis; CARD™ There is also evidence that the drug Modafinil, a substance analysis to establish both agreement and self-restraint that acts as a selective, relatively weak, atypical dopamine throughout treatment; Natural D2 Agonistic Therapy reuptake inhibitor, has been shown to modulate dopaminergic (NAAT-KB220™); mRNA to determine pre and post transmission and produce enhanced reward- related brain candidate gene expressions in RDS patients attending activity in the NAc in healthy subjects. While there have inpatient/out-patient treatment programs. We therefore been some positive effects especially with nicotine dependence, propose a shift in clinical care to “Reward Deficiency it has abuse liability [87]. Additionally, we believe that the Solutions System (RDSS) ™” [95]. popular GABA promoting drugs like Topiramate should not be used in the long-term because of possible attenuated CONFLICT OF INTEREST dopamine release and suicide ideation [88]. The proposal Dr. Blum through his company Synaptamine owns U.S. herein is to promote long-term “dopamine homeostasis” and foreign patents on both nutraceuticals and genetic [89]. testing. The authors confirm that this article content has no There are a plethora of studies showing the relationship other conflict of interest. of many behavioral addictions and reward deficiency. One example involves the work of Han et al. [90, 91] showing ACKNOWLEDGEMENTS that both alcohol dependence (AD) and Internet Gaming The authors appreciate the expert edits by Margaret A. Disorder (IGD) subjects have positive functional connectivity Madigan and assistance of Jia A. Blum. We acknowledge the between the dorsolateral prefrontal cortex (DLPFC), grants of Marcelo Febo, recipient of R01DA019946 and R21 Common Neurogenetic Diagnosis and Meso-Limbic Manipulation Current Neuropharmacology, 2017, Vol. 15, No. 1 191

DA038009, and Rajendra D. Badgaiyan supported by the [18] Park, K; Volkow, ND; Pan, Y; Du, C Chronic cocaine dampens National Institutes of Health grants www.ncbi.nlm.nih.gov/ dopamine signaling during cocaine intoxication and unbalances D1 1R01NS073884. over D2 receptor signaling. J. Neurosci., 2013, 33(40), 15827-36. [http://dx.doi.org/10.1523/JNEUROSCI.1935-13.2013] [19] Pierce, R.C.; Kumaresan, V. The mesolimbic dopamine system: the REFERENCES final common pathway for the reinforcing effect of drugs of abuse? Neurosci. Biobehav. Rev., 2006, 30(2), 215-238. [http://dx.doi.org/ [1] Physiology or Medicine for 2000 - Press Release Nobelprize.org. 10.1016/j.neubiorev.2005.04.016] [PMID: 16099045] Nobel Media AB 2014. Web. http://www.nobelprize.org/ nobelprizes/ [20] Eipper-Mains, J.E.; Eipper, B.A.; Mains, R.E. Global Approaches medicine/laureates/2000/press.html, 2015 Apr 6 to the Role of miRNAs in Drug-Induced Changes in Gene [2] Fahn, S. The medical treatment of Parkinson disease from James Expression. Front. Genet., 2012, 3, 109. [http://dx.doi.org/ Parkinson to George Cotzias. Mov. Disord, 2015, 30(1), 4-18. 10.3389/fgene.2012.00109] [PMID: 22707957] [http://dx.doi.org/10.1002/mds.26102] [PMID: 25491387] [21] Barbierato, M.; Zusso, M.; Skaper, S.D.; Giusti, P. MicroRNAs: [3] Kemp, D.E. Managing the side effects associated with commonly emerging role in the endogenous µ opioid system. CNS Neurol. used treatments for bipolar depression. J. Affect. Disord., 2014, Disord. Drug Targets, 2015, 14(2), 239-250. [http://dx.doi.org/ 169(Suppl. 1), S34-S44. [http://dx.doi.org/10.1016/S0165-0327(14) 10.2174/1871527314666150116123932] [PMID: 25613510] 70007-2] [PMID: 25533913] [22] He, Y; Wang, ZJ Let-7 microRNAs and Opioid Tolerance. Front [4] Furukawa, T.A.; Levine, S.Z.; Tanaka, S.; Goldberg, Y.; Samara, Genet, 2012, 3, 110. eCollection 2012 [http://dx.doi.org/10.3389/ M.; Davis, J.M.; Cipriani, A.; Leucht, S. Initial severity of fgene.2012.00110] schizophrenia and efficacy of antipsychotics: participant-level [23] Most, D; Workman, E; Harris, RA Synaptic adaptations by alcohol meta-analysis of 6 placebo-controlled studies. JAMA Psychiatry, and drugs of abuse: changes in microRNA expression and mRNA 2015, 72(1), 14-21. [http://dx.doi.org/10.1001/jamapsychiatry. 2014. regulation. Front. Mol. Neurosci., 2014, 7, 85. [http://dx.doi.org/ 2127] [PMID: 25372935] 10.3389/fnmol.2014.00085] [5] Goodkind, M.; Eickhoff, S.B.; Oathes, D.J.; Jiang, Y.; Chang, A.; [24] Bali, P; Kenny, P.J. MicroRNAs and Drug Addiction. Front Jones-Hagata, L.B.; Ortega, B.N.; Zaiko, Y.V.; Roach, E.L.; Genet., 2013, 4, 43. [http://dx.doi.org/10.3389/fgene.2013.00043] Korgaonkar, M.S.; Grieve, S.M.; Galatzer-Levy, I.; Fox, P.T.; [25] Dreyer, J.L. New insights into the roles of microRNAs in drug Etkin, A. Identification of a common neurobiological substrate for addiction and neuroplasticity. Genome Med., 2010, 2(12), 92. mental illness. JAMA Psychiatry, 2015, 72(4), 305-315. [http://dx. [http://dx.doi.org/10.1186/gm213] [PMID: 21205279] doi.org/10.1001/jamapsychiatry.2014.2206] [PMID: 25651064] [26] Smith, D.E. The process addictions and the new ASAM definition [6] Blum, K. The effect of dopamine and other catecholamines on of addiction. J. Psychoactive Drugs, 2012, 44(1), 1-4. [http://dx. neuromuscular transmission. Arch. Int. Pharmacodyn. Ther., 1969, doi.org/10.1080/02791072.2012.662105] [PMID: 22641960] 181(2), 297-306. [PMID: 4326551] [27] Blum, K.; Wood, R.C.; Braverman, E.R.; Chen, T.J.; Sheridan, P.J. [7] Blum, K.; Calhoun, W.; Merritt, J.; Wallace, J.E. L-DOPA: effect The D2 dopamine receptor gene as a predictor of compulsive on ethanol narcosis and brain biogenic amines in mice. Nature, disease: Bayes’ theorem. Funct. Neurol., 1995, 10(1), 37-44. [PMID: 1973, 242(5397), 407-409. [http://dx.doi.org/10.1038/242407a0] 7649500] [PMID: 4735636] [28] Burger, K.S.; Stice, E. Frequent ice cream consumption is [8] Blum, K.; Eubanks, J.D.; Wallace, J.E.; Schwertner, H.A. Suppression associated with reduced striatal response to receipt of an ice cream- of ethanol withdrawal by dopamine. Experientia, 1976, 32(4), 493- based milkshake. Am. J. Clin. Nutr., 2012, 95(4), 810-817. 495. [http://dx.doi.org/10.1007/BF01920816] [PMID: 944645] [http://dx.doi.org/10.3945/ajcn.111.027003] [PMID: 22338036] [9] Blum, K.; Wallace, J.E.; Schwerter, H.A.; Eubanks, J.D. Morphine [29] Stice, E.; Yokum, S.; Blum, K.; Bohon, C. Weight gain is suppression of ethanol withdrawal in mice. Experientia, 1976, associated with reduced striatal response to palatable food. J. 32(1), 79-82. [http://dx.doi.org/10.1007/BF01932634] [PMID: 942927] Neurosci., 2010, 30(39), 13105-13109. [http://dx.doi.org/10.1523/ [10] Davis, V.E.; Walsh, M.J. Alcohol addiction and tetrahydro- JNEUROSCI.2105-10.2010] [PMID: 20881128] papaveroline. Science, 1970, 169(3950), 1105-1106. [PMID: 5465179] [30] Dunn, J.P.; Kessler, R.M.; Feurer, I.D.; Volkow, N.D.; Patterson, [11] Blum, K., Ed.; Alcohol & Opiates: Neurochemical and Behavioral B.W.; Ansari, M.S.; Li, R.; Marks-Shulman, P.; Abumrad, N.N. Actions; Relationship of dopamine type 2 receptor binding potential with [12] Melchior, C.L.; Myers, R.D. Genetic differences in ethanol fasting neuroendocrine hormones and insulin sensitivity in human drinking of the rat following injection of 6-OHDA, 5,6-DHT or obesity. Diabetes Care, 2012, 35(5), 1105-1111. [http://dx.doi.org/ 5,7-DHT into the cerebral ventricles. Pharmacol. Biochem. Behav., 10.2337/dc11-2250] [PMID: 22432117] 1976, 5(1), 63-72. [http://dx.doi.org/10.1016/0091-3057(76)90289- [31] Johnson, P.M.; Kenny, P.J. Dopamine D2 receptors in addiction- 6] [PMID: 996042] like reward dysfunction and compulsive eating in obese rats. [13] Dackis, C.A.; Gold, M.S. New concepts in cocaine addiction: the Nat. Neurosci., 2010, 13(5), 635-641. [http://dx.doi.org/10.1038/ dopamine depletion hypothesis. Neurosci. Biobehav. Rev., 1985, nn.2519] [PMID: 20348917] 9(3), 469-477. [http://dx.doi.org/10.1016/0149-7634(85)90022-3] [32] Cordeira, J.; Rios, M. Weighing in the role of BDNF in the [PMID: 2999657] central control of eating behavior. Mol. Neurobiol., 2011, 44(3), [14] Ng Cheong Ton, J.M.; Gerhardt, G.A.; Friedemann, M.; Etgen, 441-448. [http://dx.doi.org/10.1007/s12035-011-8212-2] [PMID: A.M.; Rose, G.M.; Sharpless, N.S.; Gardner, E.L. The effects of 22012072] delta 9-tetrahydrocannabinol on potassium-evoked release of [33] Lobo, M.K.; Covington, H.E., III; Chaudhury, D.; Friedman, A.K.; dopamine in the rat caudate nucleus: an in vivo electrochemical and Sun, H.; Damez-Werno, D.; Dietz, D.M.; Zaman, S.; Koo, J.W.; in vivo microdialysis study. Brain Res., 1988, 451(1-2), 59-68. Kennedy, P.J.; Mouzon, E.; Mogri, M.; Neve, R.L.; Deisseroth, K.; [http://dx.doi.org/10.1016/0006-8993(88)90749-4] [PMID: 2855215] Han, M.H.; Nestler, E.J. Cell type-specific loss of BDNF signaling [15] Blum, K.; Kozlowski, G.P. Ethanol and neuromodulator mimics optogenetic control of cocaine reward. Science, 2010, interactions: a cascade model of reward. Prog. Alcohol Res., 1990, 330(6002), 385-390. [http://dx.doi.org/10.1126/science.1188472] 2, 131-149. [PMID: 20947769] [16] Blum, K.; Noble, E.P.; Sheridan, P.J.; Montgomery, A.; Ritchie, T.; [34] Barr, C.L.; Kidd, K.K. Population frequencies of the A1 allele at Jagadeeswaran, P.; Nogami, H.; Briggs, A.H.; Cohn, J.B. Allelic the dopamine D2 receptor locus. Biol. Psychiatry, 1993, 34(4), 204- association of human dopamine D2 receptor gene in alcoholism. 209. [http://dx.doi.org/10.1016/0006-3223(93)90073-M] [PMID: JAMA, 1990, 263(15), 2055-2060. [http://dx.doi.org/10.1001/jama. 8399816] 1990.03440150063027] [PMID: 1969501] [35] Palomo, T.; Archer, T.; Kostrzewa, R.M.; Beninger, R.J. [17] Blum, K.; Gold, M.S. Neuro-chemical activation of brain reward Comorbidity of substance abuse with other psychiatric disorders. meso-limbic circuitry is associated with relapse prevention and Neurotox. Res., 2007, 12(1), 17-27. [http://dx.doi.org/10.1007/ drug hunger: a hypothesis. Med. Hypotheses, 2011, 76(4), 576-584. BF03033898] [PMID: 17513197] [http://dx.doi.org/10.1016/j.mehy.2011.01.005] [PMID: 21306831] 192 Current Neuropharmacology, 2017, Vol. 15, No. 1 Blum et al.

[36] Blum, K.; Sheridan, P.J.; Wood, R.C.; Braverman, E.R.; Chen, size is small. Alcohol Alcohol., 2006, 41(5), 479-485. [http://dx.doi. T.J.; Comings, D.E. Dopamine D2 receptor gene variants: org/10.1093/alcalc/agl043] [PMID: 16751215] association and linkage studies in impulsive-addictive-compulsive [50] Gullo, M.J.; St John, N.; McD Young, R.; Saunders, J.B.; Noble, behaviour. Pharmacogenetics, 1995, 5(3), 121-141. [http://dx.doi. E.P.; Connor, J.P.; Connor, J.P. Impulsivity-related cognition in org/10.1097/00008571-199506000-00001] [PMID: 7550364] alcohol dependence: Is it moderated by DRD2/ANKK1 gene [37] Blum, K.; Chen, A.L.; Giordano, J.; Borsten, J.; Chen, T.J.; Hauser, status and executive dysfunction? Addict. Behav., 2014, 39(11), M.; Simpatico, T.; Femino, J.; Braverman, E.R.; Barh, D. The 1663-1669. [http://dx.doi.org/10.1016/j.addbeh.2014.02.004] [PMID: addictive brain: all roads lead to dopamine. J. Psychoactive Drugs, 24629326] 2012, 44(2), 134-143. [http://dx.doi.org/10.1080/02791072.2012. [51] Berggren, U.; Fahlke, C.; Berglund, K.J.; Wadell, K.; Zetterberg, 685407] [PMID: 22880541] H.; Blennow, K.; Thelle, D.; Balldin, J. Dopamine D2 receptor [38] Wang, G.J.; Smith, L.; Volkow, N.D.; Telang, F.; Logan, J.; genotype is associated with increased mortality at a 10-year follow- Tomasi, D.; Wong, C.T.; Hoffman, W.; Jayne, M.; Alia-Klein, N.; up of alcohol-dependent individuals. Alcohol Alcohol., 2010, 45(1), Thanos, P.; Fowler, J.S. Decreased dopamine activity predicts 1-5. [http://dx.doi.org/10.1093/alcalc/agp041] [PMID: 19654188] relapse in methamphetamine abusers. Mol. Psychiatry, 2012, 17(9), [52] Dahlgren, A.; Wargelius, H.L.; Berglund, K.J.; Fahlke, C.; 918-925. [http://dx.doi.org/10.1038/mp.2011.86] [PMID: 21747399] Blennow, K.; Zetterberg, H.; Oreland, L.; Berggren, U.; Balldin, J. [39] Lotan, A; Fenckova, M; Bralten, J; Alttoa, A; Dixson, L; Williams, Do alcohol-dependent individuals with DRD2 A1 allele have an RW; van der Voet, M. Neuroinformatic analyses of common and increased risk of relapse? A pilot study. Alcohol Alcohol., 2011, distinct genetic components associated with major neuropsychiatric 46(5), 509-513. [http://dx.doi.org/10.1093/alcalc/agr045] [PMID: disorders. Front Neurosci., 2014, 6, 8-331. eCollection 2014 21613303] [http://dx.doi.org/10.3389/fnins.2014.00331] [53] Leventhal, A.M.; Lee, W.; Bergen, A.W.; Swan, G.E.; Tyndale, [40] Gatt, J.M.; Burton, K.L.; Williams, L.M.; Schofield, P.R. Specific R.F.; Lerman, C.; Conti, D.V. Nicotine dependence as a moderator and common genes implicated across major mental disorders: of genetic influences on smoking cessation treatment outcome. a review of meta-analysis studies. J. Psychiatr. Res., 2015, 60, Drug Alcohol Depend., 2014, 138, 109-117. [http://dx.doi.org/ 1-13. [http://dx.doi.org/10.1016/j.jpsychires.2014.09.014] [PMID: 10.1016/j.drugalcdep.2014.02.016] [PMID: 24667010] 25287955] [54] Bannon, M.J.; Johnson, M.M.; Michelhaugh, S.K.; Hartley, Z.J.; [41] Levran, O.; Randesi, M.; da Rosa, J.C.; Ott, J.; Rotrosen, J.; Halter, S.D.; David, J.A; Kapatos, G.; Schmidt, C.J. A molecular Adelson, M.; Kreek, M.J. Overlapping dopaminergic pathway profile of cocaine abuse includes the differential expression of genetic susceptibility to heroin and cocaine addictions in African genes that regulate transcription, chromatin, and dopamine cell Americans. Ann. Hum. Genet., 2015, 79(3), 188-198. [http://dx.doi. phenotype. Neuropsychopharmacology., 2014, 39(9), 2191-2199. org/10.1111/ahg.12104] [PMID: 25875614] [55] Di Ciano, P.; Grandy, D.K.; Le Foll, B. Dopamine D4 receptors in [42] Li, Z.H.; Liu, Y.F.; Li, K.N.; Duanmu, H.Z.; Chang, Z.Q.; Li, Z.Q.; psychostimulant addiction. Adv. Pharmacol., 2014, 69, 301-321. Zhang, S.Z.; Xu, Y. Analysis of functional and pathway association [http://dx.doi.org/10.1016/B978-0-12-420118-7.00008-1] [PMID: of differential co-expressed genes: a case study in drug addiction. J. 24484981] Biomed. Inform., 2012, 45(1), 30-36. [http://dx.doi.org/10.1016/ [56] Loweth, J.A.; Scheyer, A.F.; Milovanovic, M.; LaCrosse, A.L.; j.jbi.2011.08.014] [PMID: 21907308] Flores-Barrera, E.; Werner, C.T.; Li, X.; Ford, K.A.; Le, T.; Olive, [43] Levey, D.F.; Le-Niculescu, H.; Frank, J.; Ayalew, M.; Jain, N.; M.F.; Szumlinski, K.K.; Tseng, K.Y.; Wolf, M.E. Synaptic Kirlin, B.; Learman, R.; Winiger, E.; Rodd, Z.; Shekhar, A.; depression via mGluR1 positive allosteric modulation suppresses Schork, N.; Kiefer, F.; Wodarz, N.; Müller-Myhsok, B.; Dahmen, cue-induced cocaine craving. Nat. Neurosci., 2014, 17(1), 73-80. N.; Nöthen, M.; Sherva, R.; Farrer, L.; Smith, A.H.; Kranzler, [http://dx.doi.org/10.1038/nn.3590] [PMID: 24270186] H.R.; Rietschel, M.; Gelernter, J.; Niculescu, A.B. Genetic risk [57] Schank, J.R.; King, C.E.; Sun, H.; Cheng, K.; Rice, K.C.; Heilig, prediction and neurobiological understanding of alcoholism. M.; Weinshenker, D.; Schroeder, J.P. The role of the neurokinin-1 Transl. Psychiatry, 2014, 4, e391. [http://dx.doi.org/10.1038/ receptor in stress-induced reinstatement of alcohol and cocaine tp.2014.29] [PMID: 24844177] seeking. Neuropsychopharmacology, 2014, 39(5), 1093-1101. [44] Pearson-Fuhrhop, K.M.; Dunn, E.C.; Mortero, S.; Devan, W.J.; [http://dx.doi.org/10.1038/npp.2013.309] [PMID: 24173499] Falcone, G.J.; Lee, P.; Holmes, A.J.; Hollinshead, M.O.; Roffman, [58] Xu, K.; Seo, D.; Hodgkinson, C.; Hu, Y.; Goldman, D.; Sinha, R. A J.L.; Smoller, J.W.; Rosand, J.; Cramer, S.C. Dopamine genetic variant on the kappa opioid receptor gene (OPRK1) is associated risk score predicts depressive symptoms in healthy adults and with stress response and related drug craving, limbic brain adults with depression. PLoS One, 2014, 9(5), e93772. [http://dx. activation and cocaine relapse risk. Transl. Psychiatry, 2013, 3, doi.org/10.1371/journal.pone.0093772] [PMID: 24834916] e292. [http://dx.doi.org/10.1038/tp.2013.62] [PMID: 23962922] [45] Kember, R.L.; Georgi, B.; Bailey-Wilson, J.E.; Stambolian, D.; [59] Xu, K.; Seo, D.; Hodgkinson, C.; Hu, Y.; Goldman, D.; Sinha, R. Paul, S.M.; Bućan, M. Copy number variants encompassing Antecedents and consequences of drug abuse in rats selectively Mendelian disease genes in a large multigenerational family bred for high and low response to novelty. Neuropharmacology, segregating bipolar disorder. BMC Genet., 2015, 16(1), 27. 2013, 76(Pt B), 425-36. [http://dx.doi.org/10.1186/s12863-015-0184-1] [PMID: 25887117] [60] Miguéns, M.; Botreau, F.; Olías, O.; Del Olmo, N.; Coria, S.M.; [46] Luhar, R.B.; Sawyer, K.S.; Gravitz, Z.; Ruiz, S.M.; Oscar-Berman, Higuera-Matas, A.; Ambrosio, E. Genetic differences in the M. Brain volumes and neuropsychological performance are related modulation of accumbal glutamate and γ-amino butyric acid levels to current smoking and alcoholism history. Neuropsychiatr. after cocaine-induced reinstatement. Addict. Biol., 2013, 18(4), 623- Dis. Treat., 2013, 9, 1767-1784. [http://dx.doi.org/10.2147/NDT. 632. [http://dx.doi.org/10.1111/j.1369-1600.2011.00404.x] [PMID: S52298] [PMID: 24273408] 22004520] [47] Ruiz, S.M.; Oscar-Berman, M.; Sawyer, K.S.; Valmas, M.M.; [61] Blum, K.; Oscar-Berman, M.; Jacobs, W.; McLaughlin, T.; Gold, Urban, T.; Harris, G.J. Drinking history associations with regional M.S. Buprenorphine Response as a Function of Neurogenetic white matter volumes in alcoholic men and women. Alcohol. Clin. Polymorphic Antecedents: Can Dopamine Genes Affect Clinical Exp. Res., 2013, 37(1), 110-122. [http://dx.doi.org/10.1111/j.1530- Outcomes in Reward Deficiency Syndrome (RDS)? J. Addict. Res. 0277.2012.01862.x] [PMID: 22725728] Ther., 2014, 5, 1000185. [http://dx.doi.org/10.4172/2155-6105. [48] Insel, T.R. Mental disorders in childhood: shifting the focus from 1000185] [PMID: 25664200] behavioral symptoms to neurodevelopmental trajectories. JAMA, [62] Ujike, H.; Katsu, T.; Okahisa, Y.; Takaki, M.; Kodama, M.; Inada, 2014, 311(17), 1727-1728. [http://dx.doi.org/10.1001/jama.2014. T.; Uchimura, N.; Yamada, M.; Iwata, N.; Sora, I.; Iyo, M.; Ozaki, 1193] [PMID: 24794359] N.; Kuroda, S. Genetic variants of D2 but not D3 or D4 dopamine [49] Berggren, U.; Fahlke, C.; Aronsson, E.; Karanti, A.; Eriksson, M.; receptor gene are associated with rapid onset and poor prognosis of Blennow, K.; Thelle, D.; Zetterberg, H.; Balldin, J. The taqI DRD2 methamphetamine psychosis. Prog. Neuropsychopharmacol. Biol. A1 allele is associated with alcohol-dependence although its effect Psychiatry, 2009, 33(4), 625-629. [http://dx.doi.org/10.1016/ j.pnpbp.2009.02.019] [PMID: 19275926] Common Neurogenetic Diagnosis and Meso-Limbic Manipulation Current Neuropharmacology, 2017, Vol. 15, No. 1 193

[63] Balldin, J.; Berggren, U.; Berglund, K.; Fahlke, C. [Why some 19(3), 317-355. [http://dx.doi.org/10.2174/092986712803414231] people relapse in alcohol dependence. There is a relation to a [PMID: 22335511] specific gene variant in the dopamine system and to psychology]. [77] Calipari, E.S.; Bagot, R.C.; Purushothaman, I.; Davidson, T.J.; Lakartidningen, 2013, 110(1-2), 21-23. [PMID: 23373179] Yorgason, J.T.; Peña, C.J.; Walker, D.M.; Pirpinias, S.T.; Guise, [64] Gyollai, A.; Griffiths, M.D.; Barta, C.; Vereczkei, A.; Urbán, R.; K.G.; Ramakrishnan, C.; Deisseroth, K.; Nestler, E.J. In vivo Kun, B.; Kökönyei, G.; Székely, A.; Sasvári-Székely, M.; Blum, imaging identifies temporal signature of D1 and D2 medium spiny K.; Demetrovics, Z. The genetics of problem and pathological neurons in cocaine reward. Proc. Natl. Acad. Sci. USA, 2016, gambling: a systematic review. Curr. Pharm. Des., 2014, 20(25), 113(10), 2726-2731. [http://dx.doi.org/10.1073/pnas.1521238113] 3993-3999. [http://dx.doi.org/10.2174/13816128113199990626] [PMID: 26831103] [PMID: 24001288] [78] Golimbet, V.E.; Alfimova, M.V.; Gritsenko, I.K.; Ebstein, R.P. [65] Blum, K.; Oscar-Berman, M.; Stuller, E.; Miller, D.; Giordano, J.; Relationship between dopamine system genes and extraversion and Morse, S.; McCormick, L.; Downs, W.B.; Waite, R.L.; Barh, D.; novelty seeking. Neurosci. Behav. Physiol., 2007, 37(6), 601-606. Neal, D.; Braverman, E.R.; Lohmann, R.; Borsten, J.; Hauser, M.; [http://dx.doi.org/10.1007/s11055-007-0058-8] [PMID: 17657431] Han, D.; Liu, Y.; Helman, M.; Simpatico, T. Neurogenetics and [79] Noble, E.P.; Ozkaragoz, T.Z.; Ritchie, T.L.; Zhang, X.; Belin, T.R.; Nutrigenomics of Neuro-Nutrient Therapy for Reward Deficiency Sparkes, R.S. D2 and D4 dopamine receptor polymorphisms and Syndrome (RDS): Clinical Ramifications as a Function of personality. Am. J. Med. Genet., 1998, 81(3), 257-267. [http://dx.doi. Molecular Neurobiological Mechanisms. J. Addict. Res. Ther., org/10.1002/(SICI)1096-8628(19980508)81:3<257::AID- 2012, 3(5), 139. [PMID: 23926462] AJMG10>3.0.CO;2-E] [PMID: 9603615] [66] Li, C.Y.; Mao, X.; Wei, L. Genes and (common) pathways [80] Doran, N.; Schweizer, C.A.; Myers, M.G.; Greenwood, T.A. A underlying drug addiction. PLOS Comput. Biol., 2008, 4(1), e2. prospective study of the effects of the DRD2/ANKK1 TaqIA [http://dx.doi.org/10.1371/journal.pcbi.0040002] [PMID: 18179280] polymorphism and impulsivity on smoking initiation. Subst. [67] Blum, K.; Chen, A.L.; Chen, T.J.; Rhoades, P.; Prihoda, T.J.; Use Misuse, 2013, 48(1-2), 106-116. [http://dx.doi.org/10.3109/ Downs, B.W.; Waite, R.L.; Williams, L.; Braverman, E.R.; 10826084.2012.733791] [PMID: 23153044] Braverman, D.; Arcuri, V.; Kerner, M.; Blum, S.H.; Palomo, T. [81] Iordanidou, M.; Tavridou, A.; Petridis, I.; Kyroglou, S.; LG839: anti-obesity effects and polymorphic gene correlates of Kaklamanis, L.; Christakidis, D.; Manolopoulos, V.G. Association reward deficiency syndrome. Adv. Ther., 2008, 25(9), 894-913. of polymorphisms of the serotonergic system with smoking [http://dx.doi.org/10.1007/s12325-008-0093-z] [PMID: 18781289] initiation in Caucasians. Drug Alcohol Depend., 2010, 108(1-2), 70- [68] Satoshi Ikemoto Brain reward circuitry beyond the mesolimbic 76. [http://dx.doi.org/10.1016/j.drugalcdep.2009.11.015] [PMID: dopamine system: A neurobiological theory. Neurosci. Biobehav. 20060656] Rev., 35(2), 129-150. [http://dx.doi.org/10.1016/j.neubiorev.2010. [82] Grzywacz, A.; Jasiewicz, A.; Małecka, I.; Suchanecka, A.; 02.001] Grochans, E.; Karakiewicz, B.; Samochowiec, A.; Bieńkowski, P.; [69] Koob, G.F. Neurocircuitry of alcohol addiction: synthesis from Samochowiec, J. Influence of DRD2 and ANKK1 polymorphisms animal models. Handb. Clin. Neurol., 2014, 125, 33-54. [http://dx. on the manifestation of withdrawal syndrome symptoms in alcohol doi.org/10.1016/B978-0-444-62619-6.00003-3] [PMID: 25307567] addiction. Pharmacol. Rep., 2012, 64(5), 1126-1134. [http://dx.doi. [70] Blum, K.; Febo, M.; McLaughlin, T.; Cronjé, F.J.; Han, D.; Gold, org/10.1016/S1734-1140(12)70909-X] [PMID: 23238469] S.M. Hatching the behavioral addiction egg: Reward Deficiency [83] Volkow, N.D.; Frieden, T.R.; Hyde, P.S.; Cha, S.S. Medication- Solution System (RDSS)™ as a function of dopaminergic assisted therapies--tackling the opioid-overdose epidemic. N. Engl. neurogenetics and brain functional connectivity linking all J. Med., 2014, 370(22), 2063-2066. [http://dx.doi.org/10.1056/ addictions under a common rubric. J. Behav. Addict., 2014, 3(3), NEJMp1402780] [PMID: 24758595] 149-156. [http://dx.doi.org/10.1556/JBA.3.2014.019] [PMID: [84] Lai, M.; Chen, W.; Zhu, H.; Zhou, X.; Liu, H.; Zhang, F.; Zhou, W. 25317338] Low dose risperidone attenuates cue-induced but not heroin- [71] Blum, K.; Oscar-Berman, M.; Demetrovics, Z.; Barh, D.; Gold, induced reinstatement of heroin seeking in an animal model of M.S. Genetic Addiction Risk Score (GARS): molecular relapse. Int. J. Neuropsychopharmacol., 2013, 16(7), 1569-1575. neurogenetic evidence for predisposition to Reward Deficiency [http://dx.doi.org/10.1017/S1461145712001563] [PMID: 23331426] Syndrome (RDS). Mol. Neurobiol., 2014, 50(3), 765-796. [85] Willuhn, I.; Burgeno, L.M.; Groblewski, P.A.; Phillips, P.E. [http://dx.doi.org/10.1007/s12035-014-8726-5] [PMID: 24878765] Excessive cocaine use results from decreased phasic dopamine [72] Blum, K.; Han, D.; Femino, J.; Smith, D.E.; Saunders, S.; signaling in the striatum. Nat. Neurosci., 2014, 17(5), 704-709. Simpatico, T.; Schoenthaler, S.J.; Oscar-Berman, M.; Gold, M.S. [http://dx.doi.org/10.1038/nn.3694] [PMID: 24705184] Systematic evaluation of “compliance” to prescribed treatment [86] Badgaiyan, R.D.; Sinha, S.; Sajjad, M.; Wack, D.S. Attenuated medications and “abstinence” from psychoactive drug abuse in Tonic and Enhanced Phasic Release of Dopamine in Attention chemical dependence programs: data from the comprehensive Deficit Hyperactivity Disorder. PLoS One, 2015, 10(9), e0137326. analysis of reported drugs. PLoS One, 2014, 9(9), e104275. [See [http://dx.doi.org/10.1371/journal.pone.0137326] [PMID: 26422146] comment in PubMed Commons below]. [http://dx.doi.org/10.1371/ [87] Robertson, P., Jr; Hellriegel, E.T. Clinical pharmacokinetic profile journal.pone.0104275] [PMID: 25247439] of modafinil. Clin. Pharmacokinet., 2003, 42(2), 123-137. [http://dx. [73] Blum, K.; Liu, Y.; Wang, W.; Wang, Y.; Zhang, Y.; Oscar- doi.org/10.2165/00003088-200342020-00002] [PMID: 12537513] Berman, M.; Smolen, A.; Febo, M.; Han, D.; Simpatico, T.; Cronjé, [88] Olmsted, C.L.; Kockler, D.R. Topiramate for alcohol dependence. F.J.; Demetrovics, Z.; Gold, M.S. rsfMRI effects of KB220Z™ on Ann. Pharmacother., 2008, 42(10), 1475-1480. [http://dx.doi.org/ neural pathways in reward circuitry of abstinent genotyped heroin 10.1345/aph.1L157] [PMID: 18698008] addicts. Postgrad. Med., 2015, 127(2), 232-241. [http://dx.doi.org/ [89] Blum, K; Febo, M; Fahlke, C; Archer, T; Berggren, U; 10.1080/00325481.2015.994879] [PMID: 25526228] Demetrovics, Z; Dushaj, K; Badgaiyan, RD Hypothesizing [74] Blum, K.; Badgaiyan, R.D.; Anges, D.H.; Gold, M.S. Should We Balancing Endorphinergic and Glutaminergic Systems to Treat and Embrace Vaccines for Treating Substance-Related Disorder, A Prevent Relapse to Reward Deficiency Behaviors: Coupling D- Subset of Reward Deficiency Syndrome (RDS)? J. Reward. Defic. Phenylalanine and N-Acetyl-L-Cysteine (NAC) as a Novel Syndr., 2015, 1(1), 3-5. [http://dx.doi.org/10.17756/jrds.2015-001] Therapeutic Modality. Clin. Med. Rev. Case Rep., 2015, 2(8), 076. [75] Blum, K.; Thanos, P.K.; Badgaiyan, R.D.; Febo, M.; Oscar- Berman, [90] Han, J.W.; Han, D.H.; Bolo, N.; Kim, B.; Kim, B.N.; Renshaw, M.; Fratantonio, J.; Demetrovics, Z.; Gold, M.S. Neurogenetics and P.F. Differences in functional connectivity between alcohol Gene Therapy for Reward Deficiency Syndrome (RDS): Are dependence and internet gaming disorder. Addict. Behav., 2015, 41, we going to the Promised Land? Cur. Exp. Opin. Biol. Ther., 2015, 12-19. [http://dx.doi.org/10.1016/j.addbeh.2014.09.006] [PMID: 15(7), 973-85. 25282597] [76] Filip, M.; Zaniewska, M.; Frankowska, M.; Wydra, K.; Fuxe, K. [91] Han, D.H.; Kim, S.M.; Bae, S.; Renshaw, P.F.; Anderson, J.S. The importance of the adenosine A(2A) receptor-dopamine D(2) Brain connectivity and psychiatric comorbidity in adolescents with receptor interaction in drug addiction. Curr. Med. Chem., 2012, 194 Current Neuropharmacology, 2017, Vol. 15, No. 1 Blum et al.

Internet gaming disorder. Addict. Biol., 2015, 2015(Dec), 22. 2016, 357(2), 264-272. [http://dx.doi.org/10.1124/jpet.115.230771] [PMID: 26689148] [PMID: 26945087] [92] Piechota, M.; Korostynski, M.; Solecki, W.; Gieryk, A.; Slezak, [94] Hikida, T.; Kimura, K.; Wada, N.; Funabiki, K.; Nakanishi, S. M.; Bilecki, W.; Ziolkowska, B.; Kostrzewa, E.; Cymerman, I.; Distinct roles of synaptic transmission in direct and indirect striatal Swiech, L.; Jaworski, J.; Przewlocki, R. The dissection of pathways to reward and aversive behavior. Neuron, 2010, 66(6), transcriptional modules regulated by various drugs of abuse in the 896-907. [http://dx.doi.org/10.1016/j.neuron.2010.05.011] [PMID: mouse striatum. Genome Biol., 2010, 11(5), R48. [http://dx.doi. 20620875] org/10.1186/gb-2010-11-5-r48] [PMID: 20459597] [95] Blum, K.; Febo, M.; Thanos, P.K.; Baron, D.; Fratantonio, J.; Gold, [93] Kononoff Vanhanen, J.; Nuutinen, S.; Tuominen, M.; Panula, P. M. Clinically Combating Reward Deficiency Syndrome (RDS) Histamine H3 Receptor Regulates Sensorimotor Gating and with Dopamine Agonist Therapy as a Paradigm Shift: Dopamine Dopaminergic Signaling in the Striatum. J. Pharmacol. Exp. Ther., for Dinner? Mol. Neurobiol., 2015, 52(3), 1862-1869. [http://dx. doi.org/10.1007/s12035-015-9110-9] [PMID: 25750061]